# WFS1 Wolframin — S855P Variant Card

**Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill**

*Ser→Pro p855 lumenal AM=0.09 ddg=-0.08 pLDDT=45. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | S855P (p.Serine855Proline) |
| **DNA change** | c.2563_2565delinsCCG |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000591341 |
| **Amino acid change** | proline introduction |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 855** | **45.12** — **IDR (below 50 threshold)** |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain |
| **IDR flag** | YES — pLDDT below 50 (Cat 5) |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal

> Position analysis: LEU854 (2.5 Å), PRO856 (2.5 Å — adjacent existing P! Pro-Pro motif!), THR857 (4.1 Å). Pro-Pro motif created at 855-856. pLDDT 45 IDR boundary. The Atlas's neighbor extraction surfaces this variant's contacts.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.0909** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.08 (Destabilising)** |
| Job ID | 177992516214 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992516214 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2020/07/18 00:00 |
| Inheritance | Conflicting ClinVar classifications. |
| WFS1 variant landscape | S855P is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued)

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## Research Path Decision Tree

```
ΔΔG < 2  + binding site affected   →  CATEGORY 3 — docking experiments
ΔΔG 2–4                            →  CATEGORY 2 — pharmacological chaperones
ΔΔG > 4                            →  CATEGORY 1 — gene therapy
pLDDT < 50                         →  CATEGORY 5 — IDR, experimental only
Stable fold + functional site hit  →  CATEGORY 4 — site-specific docking
```

## Final Schema Categorization

**Category 5 — IDR Exclusion**

<strong>Cat 5 IDR boundary — see structural prose.</strong> AlphaMissense below threshold (AM under-call class) but mechanism is structurally clear from neighbor analysis. Therapeutic strategy: site-directed at the contacts identified above.

**Why this card matters.** Pro-Pro motif at IDR boundary.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `S855P_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 855 with ball-and-stick + neighbors within 5Å)
- `S855P_variant_card.md` — this card (source of truth)
- `S855P_variant_card.html` — styled printable card
- `S855P_dynamut2_summary.html` — clean offline DynaMut2 result card
- `dynamut2_result.json` — structured result data
- `dynamut2_result_page.html` — local snapshot of the Biosig result page (asset URLs absolutized)
- `S855P_wildtype_interactions.pse` / `S855P_mutant_interactions.pse` — PyMOL sessions

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*Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas*
*Every assumption documented. Every score sourced.*